We propose to conduct a randomized clinical trial among women who have/have not been vaccinated against HPV 16/18, to compare the sensitivity, specificity, cost-effectiveness and acceptability of screening for CIN 2- 3/CIS using the currently recommended cytology-based screening approach and a novel approach in which self collected samples are tested for high risk (HR)-HPV DNA followed by in-clinic cytology for triage of HR- HPV positive women to colposcopy. We will also explore the potential utility of triage of HR-HPV positive women by HPV genotyping and/or detection of epigenetic changes. The significance of the proposed study is that despite the availability of prophylactic HPV 16/18 vaccines, screening will need to continue and although, in the absence of a vaccine, cytology based screening was highly effective, cost-effectiveness analyses suggest that the incremental cost-effectiveness ratio of adding vaccination to cytology-based screening will far exceed commonly-cited willingness to pay thresholds. Further, the PPV of cytology will be decreased among HPV vaccinated women. Studies in other countries suggest that HPV based screening the cytology based triage will be more sensitive and specific than cytology based screening even among women vaccinated against HR-HPV. The study is novel as HPV screening with cytology triage has not been examined in relationship to vaccination, or in combination with home based collection of specimens. Further, HPV based screening with cytology triage has not yet been examined in US based populations, and, unlike previous, we will determine the absolute, rather than the relative, sensitivity and specificity of each approach, and carry out cost effectiveness analyses based on data collected from study participants immediately after they complete screening. The potential impact of demonstrating the utility of this novel approach is the eventual widespread adoption of a more cost effective approach to CCC, appropriate to the era of HPV vaccines. Dr. Kiviat, Kulasingam, Hawes, Feng and Emerson have proven track records for successfully carrying out large, clinical trials and cost-effectiveness analyses which have challenged/changed clinical practice paradigms of CCC. PUBLIC HEALTH RELEVANCE: Developing novel sensitive, specific and cost effective approaches to cervical cancer control (CCC) for women who have/have not received the HPV vaccine is of great public health importance. This study will compare our current Pap smear based screening approach for cervical cancer control, to cervical cancer control using home based HPV screening assays. This novel approach would more cost effective than currently recommended approaches.